2628 - Double-Blind Study of Tocilizumab Plus Methotrexate Vs Tocilizumab Plus Placebo in Patients with Active Rheumatoid Arthritis Despite Prior Methotrexate: Progression of Structural Damage, Quality of Life, and Physical Function At 24 Weeks

Wednesday, November 9, 2011: 11:15 AM
W196b (McCormick Place West)
Maxime Dougados, Paris-Descartes University, Cochin Hospital, Paris, France, Karsten Kissel, F. Hoffmann-La Roche Ltd, Basel, Switzerland, Howard Amital, Sheba Medical Center, Tel-hashomer, Israel, Philip G. Conaghan, NIHR-Leeds Biomedical Research Unit and Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom, Emilio Martin-Mola, Hospital Universitario La Paz, Madrid, Spain, Evgeny L. Nasonov, Institute of Rheumatology, Moscow, Russia, Georg Schett, Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, Orrin M. Troum, USC Keck School of Medicine, Santa Monica, CA, Tiina Veldi, East-Tallinn Central Hospital, Tallinn, Estonia, Corrado Bernasconi, Roche, Basel, Switzerland and T.W.J. Huizinga, Leiden University Medical Center, Leiden, Netherlands
Presentation Number: 2628

Background/Purpose: To evaluate clinical efficacy (including progression of structural damage, quality of life (QoL), and physical function) and safety of adding tocilizumab (TCZ) to methotrexate (MTX) vs switching to TCZ alone in patients (pts) with moderate to severe active rheumatoid arthritis (RA) despite MTX treatment.

Methods: In the double-blind, 2-year study ACT-RAY (NCT00810199, EudraCT No. 2008-001847-20) patients on stable doses of oral weekly MTX were randomized to continued MTX with addition of TCZ 8 mg/kg every 4 wks or oral PBO+TCZ. The study was powered to assess the primary endpoint (DAS28 remission rate [RR] at 24 wks) for superiority of the combination arm based on a 12.5% difference between groups: 42.5% on TCZ+MTX vs 30% on TCZ+PBO. Baseline and wk-24 hand and feet radiographs were scored by independent readers blinded to treatment allocation, clinical response, and sequence of X-rays.

Summary of Results: Of 556 pts randomized (TCZ+MTX=279; TCZ+PBO=277) 92% (n=512; TCZ+MTX=260; TCZ+PBO=252) completed 24 wks. Mean baseline characteristics were similar for both groups (female, 80.3%; age, 53.3 yrs; RA duration, 8.2 yrs; DAS28, 6.35) except for radiographic scores (Table). DAS28 RR was 40.4% and 34.8% in TCZ+MTX and TCZ+PBO groups, respectively (difference between groups 5.65% [95% CI: 2.41, 13.71]; P=0.19; not significant). ACR20/50/70/90 response rates were 72%/45%/25%/6% (TCZ+MTX) and 71%/41%/26%/5% (TCZ+PBO) (all P=NS). Progression of structural damage was low, as shown by change in GSS (Table) and proportion of pts showing no progression (change ≤ 0). In analyses of covariance models, taking baseline values into account, there were no significant differences between groups. HAQ-DI and RAQoL improved significantly from baseline, with no differences between groups (Table). Rates per 100 patient-yrs of SAEs and serious infections were 21 and 6 for TCZ+MTX and 18 and 6 for TCZ+PBO, respectively; infections were the most frequent AEs and SAEs. AE-related discontinuations and dose modifications occurred in 3.9% and 27.4% of TCZ+MTX and 2.9% and 18.5% of TCZ+PBO pts, respectively. ALT elevations >60 U/L were observed in 16% and 6% of TCZ+MTX and TCZ+PBO pts, respectively.

 

Radiographic and QoL Results at Week 24

Genant-modified Sharp Score (GSS), Mean (SD)

TCZ + MTX

N=277

TCZ + PBO

N=276

Between-group Difference (95% CI)

Total GSS

Baseline

Baseline annualized progression rate

Change from baseline (wk 24)

30.4 (31.8)

3.71

0.08 (1.88)

 

37.1 (40.5)

4.47

0.22 (1.11)

 

 

 

0.13 (0.39, 0.13)

P=0.3304*

JSN Score

Baseline

Change from baseline (wk 24)

14.7 (17.3)

0.08 (1.49)

 

17.7 (21.7)

0.11 (0.70)

 

 

0.02 (0.22, 0.17)

P=0.8235*

Erosion Score

Baseline

Change from baseline (wk 24)

15.7 (15.4)

0.01 (0.79)

 

19.4 (19.8)

0.11 (0.63)

 

 

0.11 (0.23, 0.02)

P=0.0871*

No Progression in GSS (Patients with Changes ≤0), n (%)

 

 

 

Total GSS

181 (65.3)

162 (58.7)

P=0.0871

JSN Score

218 (78.7)

203 (73.6)

P=0.1319

Erosion Score

190 (68.6)

179 (64.9)

P=0.3317

QoL Data

Change From Baseline, Mean (SD)

 

 

 

HAQ-DI

0.56 (0.67)

 

0.55 (0.53)

 

P=0.9323

RAQoL

5.97 (7.95)

 

5.19 (7.06)

 

P=0.3080

*P-values are for between-group differences in adjusted means (change from baseline to wk 24) from the analysis of covariance

 

P-values are for between-group differences from a two-sided Cochran-Mantel-Haenszel test stratified for region and baseline DAS28

P-values are for between-group differences from a 2-sided Wilcoxon rank-sum test of no difference between the 2 treatment groups in change from baseline

 

Conclusions: The study did not demonstrate clinical superiority of TCZ+MTX combination therapy over TCZ monotherapy at wk 24, based on DAS28 remission rates and other efficacy endpoints. This was confirmed by near complete arrest of progression of structural damage, with no significant differences between groups, leading to significant improvement in QoL with both treatments. The safety data confirmed previous findings. TCZ combined with MTX was associated more commonly with transaminase increases. These results show that clinically meaningful responses can be obtained with TCZ monotherapy and therefore MTX may not be a required concomitant treatment with TCZ.

 


Keywords: multicenter study, rheumatoid arthritis (RA) and tocilizumab

Disclosure: M. Dougados, F. Hoffmann-La Roche Ltd, 2, F. Hoffmann-La Roche Ltd, 5 ; K. Kissel, F. Hoffmann-La Roche Ltd, 3 ; H. Amital, None; P. G. Conaghan, Centocor, Inc., 2, F. Hoffmann-La Roche Ltd, 2, AstraZeneca, 8, Bioberica, 8, Bristol-Myers Squibb, 8, Centocor, Inc., 8, Merck Pharmaceuticals, 8, Novartis Pharmaceutical Corporation, 8, Pfizer Inc, 8, F. Hoffmann-La Roche Ltd, 8 ; E. Martin-Mola, Pfizer Inc, 5, F. Hoffmann-La Roche, 5, MSD, 5, Abbott Immunology Pharmaceuticals, 5, UCB, 5, Pfizer Inc, 9, F. Hoffmann-La Roche, 9, MSD, 9, Abbott Immunology Pharmaceuticals, 9, UCB, 9 ; E. L. Nasonov, None; G. Schett, None; O. M. Troum, Genentech Inc., 2, Genentech Inc., 5 ; T. Veldi, None; C. Bernasconi, F. Hoffmann-La Roche Ltd, 3 ; T. W. J. Huizinga, Schering-Plough, 5, UCB, 5, Bristol-Myers Squibb, 5, Biotest AG, 5, Wyeth/Pfizer, 5, Novartis Pharmaceutical Corporation, 5, F. Hoffmann-La Roche Ltd, 5, Sanofi-Aventis Pharmaceutical, 5, Abbott Immunology Pharmaceuticals, 5, Crescendo Bioscience, 5, Axis-Shield Diagnostics, 5, Schering-Plough, 8, UCB, 8, Bristol-Myers Squibb, 8, Biotest AG, 8, Wyeth/Pfizer, 8, Novartis Pharmaceutical Corporation, 8, F. Hoffmann-La Roche Ltd, 8, Sanofi-Aventis Pharmaceutical, 8, Abbott Immunology Pharmaceuticals, 8, Crescendo Bioscience, 8, Axis-Shield Diagnostics, 8 .